Weight loss for overweight and obese individuals is recommended for cancer prevention; however, weight loss, particularly in older adults, can cause deleterious accelerated bone and muscle loss. A growing body of evidence suggests that vitamin D has anti-carcinogenic effects by modulating cellular growth and apoptosis, and by reducing angiogenesis. Higher dietary intake of vitamin D and circulating vitamin D metabolites have been inversely associated with risk of colon, breast and other cancers in some, but not all, epidemiological studies. In addition to its well-recognized role in bone metabolism, vitamin D also has anti-adipogenic properties which could protect against weight gain, and is positively associated with muscle strength and physical functioning, which could support the adoption of lifestyle behaviors associated with reduced cancer risk, such as exercise. A consistent inverse association is observed between obesity and serum vitamin D level which suggests that some of the associations between excess body weight or vitamin D levels with cancer risk could be due to their relationship with each other. However, the relationships between vitamin D and specific components of body composition have not been well characterized in older populations. Likewise, whether vitamin D level influences fat, muscle, and bone mass in individuals undergoing weight loss through diet and exercise is unclear. The primary Specific Aim of this proposal is to determine, within the context of an ongoing double-blind randomized controlled trial (RCT), the effect of oral vitamin D3 (cholecalciferol) supplementation (2000 IU daily) vs. placebo on body composition changes, including total and trunk fat mass (kg), % body fat, total and appendicular lean mass (kg), % lean mass, bone mineral content (g), and bone mineral density (BMD) at the spine and hip (g/cm2), in 228 overweight/obese postmenopausal women (50-75 y) undergoing a 12-month lifestyle change weight loss program through caloric restriction and aerobic exercise. Secondary aims are to: 1) examine the extent to which changes in body composition mediate associations between serum vitamin D and biomarkers of cancer risk tested in the parent RCT (insulin resistance and C-reactive protein [CRP]); and 2) examine associations between change in body composition and change in other outcomes such as strength, insulin resistance, and CRP. While the parent trial is testing effects on weight and BMI, it cannot determine how much of the change is due to specific components of body composition, which represents data of principal importance in understanding the mechanisms linking energy balance and cancer. The proposed study is highly novel as no previous RCT has tested whether vitamin D repletion can ameliorate potential adverse effects of weight loss on muscle and bone mass in postmenopausal women undergoing weight loss. Given the high prevalence and associated health risks of overweight/obesity and low vitamin D status among older adults, results of this study will have direct implications for clinical and public health practice and coud lead to a relatively simple and easily adopted intervention for cancer prevention. PUBLIC HEALTH RELEVANCE: We will determine, within the context of an ongoing randomized trial, the effect of oral vitamin D supplementation (2000 IU daily) vs. placebo on body composition changes (fat, lean, and bone mass) measured by dual x-ray absorptiometry (DXA) in postmenopausal women who are at increased risk for several cancers by virtue of being overweight and obese and having low levels of vitamin D.